ANTINEOPLASTICS I: GENERAL CONCEPTS

ESSENTIAL MATERIAL FROM OTHER LECTURES REFERENCES Katzung Basic and Clinical Pharmacology (10th ed.) Chapter 55, pg. 878-882 ESSENTIAL MATERIAL FROM OTHER LECTURES Cell division & cell cycle and apoptosis, especially cell cycle and p53 - Dr. Holy, Principles – there is a link to this material on my website DNA structure and replication - Dr. Perkins, Principles. Regulation of gene expression and Multifactorial nature of cancer – Dr. Cormier, Principles Principles of Pharmacology – Dr. Knych, Principles Cell injury and cell death and Neoplasia - Dr. Ward, Histopathology

CRITICAL FACTS

LEARNING OBJECTIVES List the potential targets and actual mechanisms of action of antineoplastic drugs. Be able to rank these with respect to specificity and be able to predict side effects based on the types of cells that are targeted by these agents. Compare and contrast the properties of cell cycle specific (CCS) and cell cycle non-specific drugs. Describe the cell kill hypothesis and its implications for treatment. Generate a mathematical appreciation for scheduling and dosing regimens used to eliminate cancer cells. List the factors that influence the success of chemotherapy and relate those factors to drug administration and choice of antineoplastic agent. List the generic mechanisms for antineoplastic drug resistance and the factors that contribute to the development of resistance. Be able to give examples of primary, acquired and multidrug resistance. Outline the strategies used in cancer chemotherapy, and be able to give an example of each.

REVIEW OF THE PROBLEM

Distinguishing Characteristics of Cancer

“Non” Evidenced Based Medicine CANCER TREATMENT cure = 5 year survival LOCAL TREATMENTS Radiation Surgery 33 CHEMOTHERAPY 17 TOTAL (1999) 5 year survival in 2003 was 62% 50

GENERAL CONCEPTS The GOAL is to eradicate the cancer cells without affecting normal tissues (the goal of DIFFERENTIAL SENSITIVITY). The REALITY is that all cytotoxic drugs affect normal tissues as well as malignancies  aim for a favourable therapeutic index.

Processes Targeted by Antineoplastic Drugs

Cells Affected by Antineoplastic Drugs that Target Rapid Cell Growth

Cell Cycle Specificity Cancer drugs can be divided into two general classes: CELL CYCLE SPECIFIC DRUGS (CCS; esp. plant alkaloids and antimetabolites), and CELL CYCLE NON-SPECIFIC DRUGS (CCNS; esp. alkylating agents and some natural products). Cell Cycle Specificity G1 M G2 S

CELL CYCLE NON-SPECIFIC DRUGS CYCLE SPECIFIC DRUGS CELL CYCLE NON-SPECIFIC DRUGS

Cell Kill Hypothesis The CELL KILL HYPOTHESIS proposes that actions of CCS drugs follow first order kinetics: a given dose kills a constant PROPORTION of a tumor cell population (rather than a constant NUMBER of cells).

Cell Kill Hypothesis Critical Points

Cell Kil Hypothesis

Factors Affecting Outcome CANCER PATIENT

Drug Resistance Resistance to cancer chemotherapeutic drugs is a major limitation to treatment. PRIMARY RESISTANCE occurs when some inherent characteristic of the cancer cells prevents the drugs from working; ACQUIRED RESISTANCE occurs when cancer cells become resistant during treatment. MULTIDRUG RESISTANCE is particularly problematic; this occurs when tumour cells become cross-resistant to a wide range of chemically dissimilar agents after exposure to a SINGLE (typically natural product) drug.

Drug Resistance Mechanisms:

Drug Resistance Contributing causes:

Multidrug Resistance (decreased accumulation)

MECHANISMS OF ACTION

PREVENT DNA SYNTHESIS DISRUPT DNA and/or PREVENT RNA SYNTHESIS Prevent nucleotide synthesis (antimetabolites) Inhibit DNA synthesizing enzymes DISRUPT DNA and/or PREVENT RNA SYNTHESIS Crosslinking agents Intercalating agents Drugs that cause DNA strand breaks INTERRUPT MITOSIS Inhibit spindle formation Enhance spindle formation IMMUNE SYSTEM MODIFIERS Immunosuppressants Cytokines and Antibodies DRUGS THAT ALTER PROTEIN FUNCTION Signal transduction inhibitors Miscellaneous ANGIOGENESIS INHIBITORS DIFFERENTIATING AGENTS DRUGS THAT INTERFERE WITH HORMONE FUNCTION SUPPORTING AGENTS